Aim
To determinate the prognostic significance of low serum C3 at the time of diagnosis of ANCA-associated vasculitis (AAV).
Methods
Our cohort included 75 consecutive patients with AAV diagnosed ...from January 2005 to December 2015. C3 levels were measured at the time of diagnosis. Patients were divided into two groups, those with low serum C3 levels (< 0.9 g/l) and those with normal serum C3 levels (0.9–1.8 g/l). We analysed association between serum C3 levels and both combined and singularly patient and renal survival (ESRD). Small number of relapsed patients did not allow for the statistical analysis to be performed as to weather the low serum C3 is associated with relapse rate in AAV patients.
Results
Low serum C3 levels were significantly associated with worse combined end-point patient and renal survival (HR 3.079; 95% CI 1.231–7.701; p = 0.016), and on multivariate adjusted analysis association remained significant (HR 2.831; 95% CI 1.093–7.338; p = 0.032). For both end-points individually low serum C3 levels were significantly associated with poorer patient survival (HR 6.378; 95% CI 2.252–18.065; p < 0.001; on multivariate adjusted analysis HR 4.315 95% CI 1.350–13.799; p = 0.014) and renal survival (HR 3.207; 95% CI 1.040–9.830; p = 0.043; on multivariate adjusted analysis HR 3.679; 95% CI 1.144–11.827; p = 0.029). In our study there was no significant association between serological and patohistological phenotypes and serum C3 levels.
Conclusion
Lower serum C3 levels at the diagnosis is associated with poorer patient and renal outcomes in AAV patients.
Small-vessel vasculitis (SVV) is the inflammation of the vessel wall that can result in hemorrhage and/or ischemia. Among the histological findings in SVV are increased infiltrating neutrophils, ...which, due to their oxidative burst and myeloperoxidase activity, release excessive reactive oxygen species, triggering a chain reaction of lipid peroxidation and yielding reactive aldehydes such as acrolein. The implication of oxidative stress in the pathogenesis of SVV was studied, focusing on acrolein immunohistochemistry in the affected skin vessels and systemic stress response. Samples from SVV patients and healthy subjects were collected and analyzed for total serum peroxides, total antioxidant capacity, inflammatory and immunological parameters, as well as for the presence of acrolein-protein adducts in the skin tissue specimens. The obtained data showed that systemic redox homeostasis and iron metabolism are altered in SVV patients. Possible biomarkers in the evaluation of oxidative status, disease activity and prevalence were indicated. Furthermore, a strong correlation between the accumulation of acrolein-protein adducts in the skin and the progression of the disease was revealed. Thus, the results of this study demonstrate that SVV is not only associated with systemic oxidative stress but also with tissue-specific oxidative stress that promotes acrolein formation and protein modification correlating with the severity of cutaneous vasculitis.
Primary forms of minimal change disease and focal segmental glomerulosclerosis are rare podocytopathies and clinically characterized by nephrotic syndrome. Glucocorticoids are the cornerstone of the ...initial immunosuppressive treatment in these two entities. Especially among adults with minimal change disease or focal segmental glomerulosclerosis, relapses, steroid dependence or resistance are common and necessitate re-initiation of steroids and other immunosuppressants. Effective steroid-sparing therapies and introduction of less toxic immunosuppressive agents are urgently needed to reduce undesirable side effects, in particular for patients whose disease course is complex. Rituximab, a B cell depleting monoclonal antibody, is increasingly used off-label in these circumstances, despite a low level of evidence for adult patients. Hence, critical questions concerning drug-safety, long-term efficacy and the optimal regimen for rituximab-treatment remain unanswered. Evidence in the form of large, multicenter studies and randomized controlled trials are urgently needed to overcome these limitations.
Purpose
To evaluate significance of clinical and histopathological prognostic factors for renal and patient outcome in AAV patient cohort.
Methods
Retrospective study included consecutive patients ...diagnosed with pauci-immune crescentic glomerulonephritis from January 2003 to December 2013. Primary outcome was combined endpoint patient death or progression to end-stage renal disease (ESRD). Secondary outcomes were patient survival and progression to ESRD (renal survival) singularly and disease relapse. Kaplan–Meyer survival analysis and multivariate Cox proportional hazard regression analysis were used to explore difference between phenotypes and finding significant predictors regarding outcomes.
Results
Out of 81 patients, 40.7% patients reached primary endpoint, 22.2% died, 29.6% reached ESRD and 16% relapsed during follow-up. Multivariate Cox proportional hazards regression-adjusted analysis found higher BVAS (HR 1.08, 95% CI 1.01–1.17,
p
= 0.042), higher baseline maximal serum creatinine (HR 1.02, 95% CI 1.01–1.03,
p
= 0.04) and lower haemoglobin (HR 0.97, 95% CI 0.95–0.99,
p
= 0.011) significantly associated with primary endpoint. Higher BVAS (HR 1.25, 95% CI 1.01–1.43,
p
= 0.001) and lower haemoglobin (HR 0.95, 95% CI 0.91–0.99,
p
= 0.008) were significantly associated with patient survival, while for renal survival, lower haemoglobin (HR 0.97, 95% CI 0.94–0.99,
p
= 0.041) and the need for acute haemodialysis (HR 3.15, 95% CI 1.20–8.26,
p
= 0.02) were significant predictors. On multivariate-adjusted analysis, no significant predictors for disease relapse were found. Kaplan–Meier survival analysis found no difference between clinical, serological and pathohistological phenotypes for all of the endpoints.
Conclusions
Renal function at presentation, anaemia and BVAS should be included in prediction models for the outcomes for the AAV patients.
Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be ...implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on
variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data.
A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the
gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR).
Eight exonic
variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters.
Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.
Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative ...glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors.
One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF.
In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10-15% of IC-MPGN/C3G patients.
To present the pathohistological and clinical characteristics of five Croatian families with Alport spectrum disorders caused by splice acceptor pathogenic variant c.193-2A>C in COL4A4 at the genomic ...position chr2:227985866.
The study enrolled five probands with kidney biopsy analysis and five family members. Mutation screening was performed with Illumina MiSeq platform. The pathogenic variant was confirmed with standard dye-terminator sequencing.
The only homozygous patient, aged two, had proteinuria and hematuria with preserved kidney function and no extrarenal manifestations. This patient had changes characteristic for Alport syndrome observed on electron microscopy of the kidney biopsy. In the heterozygous group, six patients had hematuria, four biopsied probands had proteinuria, and only one had moderately reduced kidney function. Heterozygous probands had variable kidney biopsy findings. Three patients had thin glomerular basement membrane nephropathy visible on electron microscopy and focal segmental glomerulosclerosis on light microscopy, two of them with focal lamellation on electron microscopy. One heterozygous patient had changes characteristic for Alport syndrome on electron microscopy without focal segmental glomerulosclerosis.
The homozygous patient had hematuria and proteinuria with preserved kidney function. The heterozygous patients presented with reasonably mild clinical phenotype and variable pathohistological findings.
Vasculitis is a clinicopathological entity characterized by inflammation and necrosis of blood vessels.
Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web ...of Science have been searched.
Two major autoantigens for ANCA are myeloperoxidase (MPO) and proteinase 3 (PR3), which are proteins in the primary granules of neutrophils and in the lysosomes of monocytes. They are expressed in mature neutrophils of patients with ANCA, while absent in healthy subjects.
The kidney is the most commonly affected vital organ in ANCA-associated vasculitis, and patient outcomes are largely determined by the severity of renal disease at diagnosis and by its response to treatment.
Proteinuria is the hallmark of renal disease. In essential hypertension the onset of de novo proteinuria is associated with faster rate of progression of disease. Some authors have suggested that the ...DD genotype of the angiotensin-converting enzyme (ACE) gene would be an adverse renal prognosis factor. It may also have different effects on the reduction of proteinuria by ACE inhibitors in patients with proteinuria. Observations on the association between the ACE gene polymorphism and hypertension have been inconsistent, which might be due to ethnic and geographical variations. In this study was to investigated the relationship between ACE gene polymorphism and antiproteinuric effect of ACE inhibitors (ramipril) and to evaluate the possible association between I/D polymorphism and hypertension. We recruited 66 hypertensive patients (male 42, female 24) with overt proteinuria (urinary protein excretion over 500 mg/day). Patients were classified into three groups in accordance with ACE genotypes (17 DD; 35 ID; 14 II). They were treated with ramipril and prospectively followed up for one year. Various clinical parameters including age, body mass index (BMI), 24-h urine protein, creatinine, creatinine clearance (Ccr), systolic and diastolic blood pressure (SBP and DBP), mean arterial pressure (MAP) were measured in the pre- and post-treatment periods. The ACE gene insertion/deletion(I/D) polymorphisms in intron 16 were determined by PCR. Results showed that there were no significant differences in the clinical parameters such as age, gender, serum creatinine, Ccr, SBP, DBP, MAP, and daily urinary excretion of protein among three groups (P > 0.05). ID genotype patients were found to have lower BMI (p = 0.031). ACE inhibition significantly reduced proteinuria in all genotype groups (p < 0.05). The percentage reductions of 24-h urinary excretion of protein were significantly different between the genotype groups (p = 0.042) and for DD genotype were significantly greater than in ID (79.2 +/- 28.9% vs 49.2 +/- 64.8%, P = 0.015). The slope of SBP was the main factor related to the slope of the percentage reduction of proteinuria, however, a significant negative correlation coefficient between these parameters was found (rs = -0.382, p = 0.002). We failed to find significant difference in outcomes of treatments with ACE inhibitor between male and female according the I/D polymorphism of the ACE gene. D allele in the ACE genotype could be a useful genetic marker with important clinical, therapeutic and prognostic implications in recognizing patients with proteinuria that are at greater risk of renal damage.
Abstract Background and Aims Our aim was to investigate the prevalence of venous thromboembolic events (VTE) in a cohort of patients with ANCA-associated vasculitis (AAV) and define factors ...associated with the frequency of VTE considering there is data on high incidence of VTE in AAV patients. In these cohorts VTE occurred mostly early in the course of disease. Method This study included 114 consecutive AAV patients with biopsy proven renal involvement in the period from 2007-2017. Patients were classified according to clinical: granulomatosis with poliangitis (GPA), microscopic polingitis (MPA) and eosinophilic granulomatosis with poliangitis (EGPA) and serological phenotype: MPO-ANCA positive, PR3-ANCA positive, MPO- and PR3-ANCA positive and ANCA-negative. Ordinal variables were analysed using logistical regression test. Statistical analysis was done in MedCalc Statistical Software version 18.11.6 (MedCalc Software Bvba, Ostend, Belgium). Results In the cohort there were 64 (56%) females, mean age was 58 (IQR 16-84) with mean follow up time 46.9 months (IQR 1-127). Clinically there were 84 (73%) patients with MPA, 26 (22%) with GPA and 4 (5%) with EGPA. Serologically there were 20% PR3-ANCA, 54% MPO-ANCA, 8% MPO- and PR-3 ANCA positive patients and 18% ANCA-negative patients. Mean serum creatinine levels (SCr) was 380.9 μmol/l (IQR 65-1402). Mean BVAS (Brimingham vasculitis score) at the time of diagnosis of AAV was 17 (IQR 5-50) and at the time of VTE 0, 9 (0-22). Mean body weight was 71kg (IQR 48-110) and mean CRP was 84 mg/ml (IQR 0, 3-256). During the follow up 7 (6.14%) of the patients had VTE, with 4 having VTE in first month after the diagnosis and other two at month 14 and 19. Logistic regression showed the connection of weight (P = 0.0052) and CRP (0.0138) with VTE with odds ratio of 1,0829 for CRP (1.003-1.027) and 1.0150 for weight (1.0284-1.1736) respectively. There was no statistical significance for clinical or serological phenotype being associated with VTE nor for other clinical or laboratory parameters. Conclusion In our cohort patients with AAV were at risk of VTE, particularly within the first year following onset of disease. In this cohort the frequency of VTE did not depend of clinical or serological AAV phenotype, age or gender. Only CRP and body weight were associated significantly with VTE occurrence. Despite VTE rates in AAV patients, routine anticoagulation is not recommended in AAV patients, given the potential risk of bleeding complications. Prospective studies are needed to assess VTE risk stratification in AAV patients and to evaluate the both benefits and potential risks ratio of prophylactic anticoagulation in AAV patients.
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